Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity

Abstract

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60 days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB1Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60 days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB1Rs with the peripherally-restricted neutral cannabinoid CB1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6 h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB1Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB1Rs.

Metabolic Profiling of CB1 Neutral Antagonists

“…Second, elimination the H-bond acceptor moiety caused a similar reduction of binding affinity between the wild-type receptor K3.28 and the mutant ligand VCHSR (Andre & Gonthier, 2010) to 31.3±9.6n M supporting the strong H-bonding interaction. Third, when both H-bonding donor and acceptor moieties were lacking, such as in the K3.28A–VCHSR pair (Argueta & DiPatrizio, 2017), the binding affinity was similarly reduced to 35.2±1.4n M , indicating the absence of an additive effect of both mutations supporting that they participate in the same H-bond interaction (Hurst et al, 2002). …”

“…Other classes of CB1R regulators in the form of neutral antagonists, that do not change basal CB1R activity, have been revealed (Pan et al, 1998) and are the subject of study (Hurst et al, 2002, 2006; Pertwee, 2005a; Reggio, 2009; Silvestri & Di Marzo, 2012) and development (Alonso et al, 2012; Argueta & DiPatrizio, 2017; Bostroem et al, 2010; Brents et al, 2012; Franks et al, 2014; Fride et al, 2007; Greig & Ross, 2010; Kangas et al, 2013; Makriyannis & Vemuri, 2008; Ruiu et al, 2003; Vela Hernandez & Yenes Minguez, 2009; Wargent et al, 2013; Wiley et al, 2011). …”

Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity

“…; Cluny et al . ; Argueta & DiPatrizio, ,) which is dependent on intact vagal afferent neurones (Capasso & Izzo, ; Izzo et al . ).…”

Host- and Helminth-Derived Endocannabinoids That Have Effects on Host Immunity Are Generated during Infection

“…Endocannabinoids, however, are generated throughout the body, and cannabinoid receptors are present on extraneuronal cells, including intestinal epithelial cells and immune cells (12)(13)(14). Signaling by the endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), through cannabinoid receptors on intestinal cells impacts feeding behavior (15,16), while signaling on immune cells can promote anti-inflammatory pathways (17). Despite functional effects on intestinal physiology and immune responses, no studies reported to date have investigated the role of endocannabinoids in parasite infection.…”